Varicose veins occur when the venous valves (which prevent the backflow of blood) do not work properly. As a result, the vein walls are weakened, and they can become deformed and dilated. Due to the fact that the valves do not work properly, the blood may recirculate and short-circuits may be created. Subsequently, the veins may become progressively dilated. In this way, the varicose veins can become more visible, and can be full of bends and become more voluminous. The evolution of this pathology may lead to consequences beyond the cosmetic ones, such as discoloration of the skin, pain and swelling of the extremities due to the effect of the venous hypertension.
According to the Spanish Society of Angiology and Vascular Surgery (SEACV) in Spain, varicose veins affect from 30 to 33% of the adult population in industrialized countries.
The veins most commonly affected are those located in the legs, although varicose veins may occur interiorly as well: e.g. varicose veins in the esophagus, around organs located in the pelvis (pelvic and ovarian varicose veins) or at or near the most distal part of the digestive tube, near the anus (haemorrhoids).
Nowadays, there are many different treatments and/or strategies in order to mitigate or eliminate these problems. Among them, we can find surgical methods. These surgical methods are related to the surgical extraction of the affected veins using classical surgery. This technique has been employed for over 100 years. This technique is based on making different skin incisions with subsequent clamping, ligation and stripping of the venous segments affected. This technique is performed under spinal anesthesia (infiltration of the spinal space) in order to obtain the anesthesia of both limbs, as well as with local or nerve block anesthesia to anesthetize more limited areas.
In the late 1990's, there was an important advance regarding the treatment of this disease because the varicose veins were treated with less invasive techniques such as the endovenous techniques. Among these new methods, it is important to highlight intravenous procedures that apply heat through a catheter (endolaser or radio frequency systems).
These systems were able to reduce injuries due to the fact that the methods are usually performed under ultrasound guidance. The effect to the veins was produced by the release of heat or electricity from inside the vein, thus an internal injury into the vein may be produced. This way, a thrombosis of the veins was achieved.
The other technique developed was sclerotherapy by injection of a sclerosing foam. This technique (compared to the “Endolaser” or radiofrequency therapies) is even less aggressive, less painful, and needs no anesthesia (R Van den Bos et al. Endovenous therapies varicosites of lower extremity. A meta-analysis. J Vasc Surg 2009 January; 49 (1): 230-9).
In summary, in the late 1990's and early 2000 a trend was found to minimize the aggressiveness varicose veins treatments. Of all the new emerged techniques, the sclerotherapy seems to be the less invasive and the one which can be applied to practically any type of varicose veins.
For this reason, in recent years, this procedure has been developed a lot and it has been found a growing interest from the scientific community in order to obtain methods suitable for the manufacture of a foam in a safe and convenient way.
Sclerotherapy involves the injection of a liquid with the ability to irritate the vascular endothelium (a thin layer or lining inside the vein that is in contact with the bloodstream).
This drug or liquid medicine can become a foam when shaken. The products internationally approved for this use are lauromacrogol (also known named as polidocanol and commercially available as etoxiesclerol), and sodium tetradecyl sulfate.
The advantage of using such a product as a foam is based on the enhancement of its effect due to the larger contact surface with the endothelial wall. The larger contact surface offers the possibility of dose reduction. Also the visibility of the drug as a foam using ultrasounds through the ultrasound scanner is improved (Schadeck M, Allaert FA. Duplex scanning in the mechanism of the sclerotherapy: Importance of the spasm. Phlebology 1995; Suppl1: 574-576).
The effect produced by the foam on the endothelium involves the injury of the cell layer, thereby the thrombosis of its content is produced. Later, this vein suffers a fibrosis process (retraction and disposal) and the vein eventually may disappear after several months.
This process can be faster or slower depending on the size of the vein or the potency of the varicose agent. Therefore, it is sometimes necessary to apply several sessions on the vein.
Although there are several methods in order to eliminate or remove varicose veins, the less aggressive and disabling treatment so far, and the one which can be used for a wide variety of pathologies is the ultrasound-guided Foam Sclerotherapy using polidocanol or other sclerosing agents. Sclerotherapy is the less invasive treatment of varicose veins known today as it can be performed in a physician's office and in a completely ambulatory way. Therefore, the present disclosure is focused on the use of this technique.
Focusing on the past 50 years, one can find numerous bibliographic references using different products and techniques to treat varicose veins without surgery.
Orbach, in 1944, was one of the pioneers in the use of air injected into the vein to promote the effect of a sclerosing product. The appearance of the ultrasound and its implementation in the real-time study of the venous pathology was a revolution in the field of the phlebology.
In 1995, Dr. Juan Cabrera presented the results of the application of a foam that he had developed with his son, the pharmacist Juan Cabrera (Cabrera J. et al. “Treatment of Varicose Long Saphenous Veins of Sclerosants in Microfoam Form With: Long—term Outcomes”. Phlebology (2000) 15; 19-23). This foam was characterized by its density and high solubility thanks to the use of a mixture of physiological gases.
Furthermore, he managed to achieve a type of foam with very small and uniform bubble size, thanks to his method of using a mixer. By using a mixture of physiological gases, the foam had greater security and stability. This foam was called “microfoam” due to the small bubble size, uniformity and stability.
Shortly after, the maximum popularization of the sclerosing foam use came from Lorenzo Tessari (Tessari L., Cavezzi A., Frullini A., Preliminary experience with a new sclerosing foam in the treatment of varicose veins. Dermatol Surg 2001 January; 27 (1): 58-60) who published his experience using a foam easily manufactured through a procedure called “The Tessari Method”. The method consists in the agitation of a sclerosing liquid using two syringes connected via a three-way tap. By means of successive alternately movements with each of the syringes connected to the gas/liquid mixture, a mix of foam, located at the inner part of the syringe, was achieved. However, this manufacturing technique, in spite of being the most widespread is not the most effective, since a relatively unstable and heterogeneous foam is obtained.
In recent years numerous articles and papers have been published about safety profiles, side effects and potential complications arising from the use of these products. Thus, it appears demonstrated that the best foam used is the one whose gas is a mixture of O2/CO2 at different concentrations. With this arrangement, the solubility and diffusion in blood is very high as opposed to atmospheric gas foams. Additionally, the foam stability is linked to the size of the bubble. Also, it has been found that the foam is more stable when the bubble diameter is more homogeneous.
There are different patents related to the aforementioned therapies that describe and protect each one of the existing methods in the state of the art. Thus, we can find the Spanish patent ES2147111, relating to a device for the application of an anti-varicose treatment that is based upon injecting sclerosant products cooled to a very low temperature by carbonic liquid, and which is characterized by the fact that it is equipped with means for coupling and extracting liquid carbon from a tank that enables the liquid carbon to be applied at atmospheric pressure in a syringe containing the sclerosant product to be injected into the varicose vein.
Similarly, the international patent WO 95/00120 relates to an injectable microfoam that contains a sclerosant agent. The foam may be created by using a mixer on a sclerosing liquid.
Similarly, the patent ES 2 247 898 relates to the use of an injection of polydocanol in the form of foam for the painless removal of varicose veins by laser. This use consists of a combination of 1) prior treatment of the vascular injuries by injecting a hypermolar hyperalcoholic substance that can be injected into the vein; 2) injecting said substance in the form of a microfoam; and 3) applying to the veins the emission from an Nd-Yag laser in its basic emission (or applying any other laser that emits with a wavelength close to the resonant of the injected substance). In particular, this patent refers to said use when the substance used as the injectable substance is polidocanol in the form of microfoam. The injection of said hydroalcoholic substance in the form of microfoam makes it possible to reduce the fluidity of the laser by 40%.
The international application WO2006120461 is related to a device configured to facilitate the preparation of therapeutic foam e.g. for the treatment of varicose veins. A pressurised vial contains a sclerosant liquid, e.g. polidocanol solution, and a sterile gas which is readily absorbed by the body, e.g. carbon dioxide, oxygen or a mixture of these gases. The vial is provided either with a specialised stopper/seal into which a syringe nozzle may be inserted or alternatively a septum seal which may be penetrated by a hypodermic needle. The quantities of gas and liquid and the pressure in the vial are pre-set so that, on connection of a syringe to the vial, a predetermined volume of both gas and liquid is transferred to the syringe, with the intention that the syringe is then used to make a foam by known means. The use of the vial ensures that the ratio of gas to liquid in the foam is standardised, and also provides a convenient way of packaging the gas and liquid and of filling the syringe in a sterile manner.
The patent ES 2 254 177 describes therapeutic sclerosing microfoams, methods and devices that have an advantage in producing a consistent profile injectable foam with minimal input by the physician yet using high volume percentages of blood dispersible gases, thus avoiding use of potentially hazardous amounts of nitrogen. The method comprises passing a mixture of a physiologically acceptable blood dispersible gas and an aqueous sclerosant liquid through one or more passages having at least one cross-sectional dimension of from 0.1 to 30 microns, the ratio of gas to liquid being controlled such that a microfoam is produced having a density of between 0.07 g/mL to 0.19 g/mL and a half-life of at least 2 minutes.
ES 2 354 695 discloses a foam transfer device, for use with aerosol canister apparatus for producing a sclerosant foam for the treatment of, inter alia, varicose veins.
WO2005048976 discloses a therapeutic foam for the treatment of, inter alia, varicose veins comprising a sclerosing solution foamed with a physiological gas such as carbon dioxide, oxygen or a mixture thereof. The foam has a nitrogen content of less than 0.8%. It may be generated using a pressurized canister system incorporating a fine mesh of micron dimensions through which the gas and sclerosing liquid are passed to make the foam. Alternatively, the foam may be generated by passing gas and solution between two syringes through a fine mesh. Techniques are described for minimizing the amount of nitrogen in a canister or syringe based product. A technique for generating and delivering foam simultaneously using a syringe based device is also disclosed.
Another interesting document is WO 00/66274. The device includes a container in which the sclerosing liquid is deposited, in addition to connecting means to a propellant gas source. Said container is hermetically closed by a head piece in which a small diameter probe tube is inserted to reduce pressure, said tube extending inside the container and being closed by a valve, whose actuation causes the outflow of the foamed sclerosing agent through an outlet provided in the head piece as a result of the propellant gas.
As has already been mentioned, although there are a lot of manufacturing systems of sclerosing foam, the most common foam (and the one which is normally used around the world) is the foam obtained with the Tessari method. However, this method has many problems of standardization and homogenization. This system consists of mixing air flow with the selected liquid, either polidocanol or sodium tetradecyl sulfate (commercially known as Sotradecol®). This foam can have medium size bubbles, but of irregular size and it becomes unstable after a few seconds of its formation. Additionally, the use of atmospheric gas as a vehicle for the sclerosing foam limits the foam administrable per session.
As mentioned above, Dr. Juan Cabrera was the pioneer in using a physiological gas mixture which provides the foam high solubility. However, in recent years many other phlebologists and vascular surgeons have developed different foam manufacturing methods. Specifically, Nick Morrison showed the low rate of undesirable effects of a foam made with a mixture of O2/CO2 (Nick Morrison. Studies on safety of foam sclerotherapy Foam Sclerotherapy. John Bergan, Van Le Cheng. Pp. 183-193 Royal Society of Medicine Press Ltd. 2008). These gases have the advantage of being dissolved and diffused safely in our organism (Nick Morrison. Comparisons of side effects using foam air and carbon dioxide for endovenous chemical ablation J Vasc Surg. 2008 Jan. 31).
The manufacture of different types of foams using commonly used medications and drugs results in great variability of foams. According to the manufacturing method used, and depending on the gas composition and the sclerosing agent, a foam of better or worse quality can be obtained.
There is therefore a need to find devices, kits, systems and methods for obtaining quality foams which are safe and can be obtained in a relatively cheap manner.